CYTOKINE ENHANCEMENT OF DNA IMMUNIZATION LEADS TO EFFECTIVE TREATMENTOF ESTABLISHED PULMONARY METASTASES

DNA immunization can result in the induction of Ag-specific cellular a nd humoral immune responses and in protective immunity in several Ag s ystems. To evaluate the utility of DNA-based immunization as a potenti al cancer treatment strategy, we employed an experimental murine tumor , CT26, expressing the model tumor-associated Ag, beta-galactosidase ( beta-gal), designated CT26,CL25. A plasmid expressing beta-gal (pCMV/b eta-gal) administered by particle-mediated gene delivery to the epider mis using a hand-held, helium-driven ''gene gun'' induced beta-gal-spe cific Ab and lytic responses. Immunization with this construct prevent ed the growth of pulmonary metastatic tumor, and the adoptive transfer of splenocytes generated by pCMV/beta-gal in vivo immunization and cu ltured in vitro with the beta-gal(876-884) immunodominant peptide redu ced the number of established pulmonary nodules. DNA immunization alon e had little or no impact on the growth of established lung metastases . To enhance the function of DNA immunization for active immunotherapy , a panel of cytokines was added as adjuvants following DNA administra tion, Significant reduction in the number of established metastases wa s observed when human rlL-2, mouse rlL-6, human rIL-7, or mouse rlL-12 were given after DNA inoculation; mouse rlL-12 as an adjuvant had the most profound effect. These findings suggest that the cytokines invol ved in the activation and expansion of lymphocyte populations may impr ove the therapeutic effects of DNA immunization. Given the ease with w hich plasmid DNA can be prepared to high purity for safe use in humans with infectious diseases and cancers, DNA immunization administered t ogether with cytokine adjuvant may be an attractive alternative to rec ombinant viral vaccines.